运动、自噬和瘦素抵抗

瘦素抵抗是人类肥胖症的主要危险因素,高瘦素水平未能抑制摄食和减轻体重,导致机体能量调节失衡。自噬是一种细胞质量控制机制,可对细胞内物质进行周转。许多人类重大疾病的发生与自噬过程有关,如肥胖症、糖尿病和神经退行性疾病等。当细胞自噬出现障碍即自噬缺陷时,会导致机体发生瘦素抵抗。研究发现,运动是维持细胞稳态的自噬有效诱导剂,机体瘦素敏感性的提高可能与运动促进细胞自噬有关,但目前尚缺乏直接证据。     

瘦素受体的研究进展

瘦素的体重调节作用是通过瘦素受体介导的。随着分子生物学技术的发展,已以受体的基因表达、结构、功能等方面取得了一些进展。肥胖患者常合并高胰岛素血症、胰岛素抵抗和瘦素抵抗,说明瘦素受体与肥胖及其相关疾病有着不可分割的联系。     

运动干预肥胖性心肌病及其机制研究进展

轻度至中度肥胖个体心脏结构和功能异常,可诱导肥胖性心肌病的发生.研究发现,运动干预是改善肥胖性心肌病的有效手段.适宜运动能降低肥胖患者心肌脂肪含量,减轻左心室心肌肥大,提高左心室舒缩功能,改善心肌病理性重塑.研究表明,适宜运动可以通过降低炎症和氧化应激、改善线粒体功能障碍、抑制脂质沉积和细胞凋亡以及调节RAS活性和mi...     

运动干预对肥胖机体体内瘦素等脂肪细胞因子作用的影响

肥胖是近年主要的流行病之一,是危害健康的全球公共卫生问题。肥胖是一种慢性低度全身性炎症,伴随着一些炎性细胞的浸润和改变,并存在脂肪细胞因子分泌紊乱。瘦素是由白色脂肪细胞分泌的一种蛋白类激素,也是促炎细胞因子,在调控体内能量与代谢等方面发挥重要作用。运动干预会使肥胖机体体内促炎因子(瘦素、TNF-α、IL-6)水平含量降低,抗炎因子(脂联素)水平含量升高。运动能够延缓肥胖机体体内炎症反应的发生。本文以体内瘦素的生理功能及作用机制为中心,系统综述了运动对肥胖性慢性炎症的调节,主要包括脂肪细胞因子瘦素、脂联素、IL-6、TNF-α,以此探讨运动干预减重降脂和减轻慢性炎症反应的机制,为防治慢性代谢性疾病提供新视角。     

MG53在运动改善胰岛素抵抗中的作用

胰岛素抵抗(insulin resistance, IR)是多种代谢性疾病的共同病理基础,运动作为改善这一病理过程的重要辅助治疗手段,其干预方式、强度和持续时间等尚未明确。MG53(mitsugumin 53)是一种近年来备受关注的骨骼肌细胞膜修复蛋白,有研究表明其不仅是"效应分子",同时也是重要的信号分子——介导多条信号转导通路发挥广泛的生物学效应。本文通过综述MG53调控胰岛素抵抗发生发展的过程,以及MG53介导运动改善胰岛素抵抗的可能信号转导机制,为运动辅助治疗胰岛素抵抗提供新思路。     

减重手术改善肥胖症认知功能障碍及其机制

越来越多的证据表明，肥胖会对大脑功能和结构产生负面影响。肥胖个体在食物线索、味觉和嗅觉、静息状态活动和功能连接方面显示出异常的神经反应，同时在决策、抑制控制、学习、记忆和注意力等认知任务中表现出异常。减重手术作为一种专门的治疗方案，可以改变消化系统解剖和生理机制，从而限制食物摄入或改变营养吸收来实现短期和长期的减重效果，改善并发症，降低死亡率，并提高生活质量。最近的研究表明，减重手术对改善肥胖症相关的认知功能障碍具有积极的影响。本文概述了肥胖与认知功能之间的关联，并重点阐述了近年来减重手术改善肥胖相关认知损伤的研究进展。涉及的内容包括奖励处理、食物摄入控制、大脑区域对认知功能的调控、大脑结构异常的恢复、激素调节改变以及对肠道微生物组成的改变，这些变化可能会影响脑功能和认知过程，这些研究成果有望为改善肥胖症患者的认知功能提供新的治疗策略和临床指导。     

运动后瘦素水平的变化及其对骨代谢的影响

瘦素(leptin)的生理作用很多,其对骨代谢的影响可以通过中枢和外周两个机制来实现.运动可以影响人体骨代谢,但运动后血清瘦素水平的变化不一,可能是因为瘦素可以通过多种下丘脑-垂体轴途径影响骨代谢,如下丘脑-垂体-肾上腺轴、下丘脑-垂体-甲状腺轴、下丘脑-垂体-生长激素轴等等,各途径作用结果不一致,致使不同的运动形式对瘦素的影响不同.本文对运动后瘦素水平改变及其对骨代谢的作用予以综述.     

微生物感染对瘦素影响的研究进展

瘦素是肥胖基因编码的一种蛋白产物,主要由白色脂肪组织产生。它在体内的主要生理功能是调节摄食和能量代谢,同时还参与多种神经－内分泌代谢系统的活动。感染是影响啮齿类动物瘦素分泌的重要因素之一,它可以影响血浆瘦素水平,从而参与影响机体的脂肪代谢;而内毒素和人类免疫缺陷病毒却并不影响人的血浆瘦素水平,但是幽门螺杆菌的感染可提高人胃基底部瘦素的表达。本文就还此作一简要回顾,并根据各类文献报道着重就感染对人和啮齿类动物血浆瘦素水平的影响作一描述。     

瘦素在糖脂代谢中的调控作用

瘦素（leptin）是OB基因的编码产物,由脂肪细胞分泌,具有广泛的生理学功能.瘦素可通过作用于中枢神经系统与外周组织等途径在糖脂代谢调控、能量代谢、生殖发育及免疫调节过程中起重要作用.不同剂量、不同作用时间,也可导致瘦素产生不同的生理学作用.近年来,随着肥胖及糖尿病在全球范围内成为流行病,瘦素在糖脂代谢中的调控作用引起了人们的广泛关注.现有的研究已发现,瘦素抵抗与胰岛素抵抗之间具有重要的关联性,揭示瘦素功能异常在肥胖诱发的糖脂代谢紊乱过程中起着重要的作用.本文将对瘦素在机体糖脂代谢中的调控作用进行综述和讨论.     

Gender Differences in the Response of Plasma Leptin Concentrations to Weight Loss in Obese Older Individuals

Plasma leptin concentration is directly related to the degree of obesity and is higher in women than in men of the same body mass index (BMI). We hypothesized that fasting plasma leptin concentrations and the response of leptin to weight loss would differ in older men and women of a similar fat mass. Plasma leptin concentrations (radioimmunoassay) and fat mass (DXA) were measured in 47 older, obese (BMI=30 ± 4 kg/m²) women and 23 older, obese (BMI=31 ± 3 kg/m²) men after a 2 to 4 week period of weight and dietary stabilization, and then in 22 of the women and 18 of the men after a 6-month weight loss intervention (250–350 kcal/d deficit). Leptin correlated with fat mass in men and women (r=0.75 and r=0.77, respectively; p values<0.0001), but women had 3-fold higher leptin levels for a given fat mass than men (p=0.01). In response to the 6-month hypocaloric diet, men and women lost a similar percentage of fat mass (?13% and ?16%, respectively), but the relative decline in circulating leptin was greater in women than men (-45% and ?21%, respectively; p<0.0001). In addition, when leptin was normalized for fat mass using the ratio method, the decrease in leptin per kilogram of fat mass was greater in women than men (-0.37 ± 0.34 vs. ?0.04 ± 0.06 ng/mL/kg; p<0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r=0.60; p<0.01), but not in women (r=0.31; p=0.17). Furthermore, the loss in fat mass correlated negatively with baseline leptin levels in women (r=-0.47; p<0.05), but not in men (r=0.03, p=NS). These results indicate that the decline in leptin concentration with weight loss correlates with the loss in fat mass in men; but, in women, other factors affect the decrease in leptin concentration. This suggests that the role of leptin in the regulation of obesity is gender-specific and may account for gender differences in response to hypocaloric treatment and maintenance of lost weight.     

Leptin transport in the central nervous system

Synthesized and released by the adipose tissue, leptin is the widely studied 167‐amino acid hormonal protein product of the obesity gene. Originally leptin was defined in association with satiety and energy balance and claimed to be an anti‐obesity factor that functioned via a feedback effect from adipocytes to hypothalamus. There is a growing body of evidence that emphasizes the importance of leptin in the regulation of food intake and body weight in animals and humans, alike. Other research findings point out that it plays a role in the regulation of the metabolism, sexual development, reproduction, hematopoiesis, immunity, gastrointestinal functions, sympathetic activation, and angiogenesis. The aim of this review is to evaluate the relation between leptin and the central nervous system (CNS). Copyright © 2009 John Wiley & Sons, Ltd.     

瘦蛋白信号转导及瘦蛋白抵抗机制

瘦蛋白(leptin)通过结合瘦蛋白受体,启动信号转导,发挥控制摄食和调节能量代谢等重要神经内分泌调节功能。肥胖症患者血浆瘦蛋白水平普遍升高,存在瘦蛋白抵抗,瘦蛋白抵抗是导致肥胖症的关键因素。本文综述了瘦蛋白信号转导作用及瘦蛋白抵抗可能的机制。     

Neuropeptide Y Expression and Endogenous Leptin Concentrations in a Dietary Model of Obesity

LAUTERIO, THOMAS J., MICHAEL J. DAVIES, MARK DEANGELO, MICHAEL PEYSER, AND JAMES LEE. Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity. Obes Res. Objective: To determine how leptin concentrations and neuropeptide (NPY) are regulated in a model of dietary obesity in relation to relative growth (RG) and relative food consumption (RFC). Research Methods and Procedures: Sprague—Dawley rats were fed a moderately high-fat diet for 14 weeks over which time animals diverged into obesity-prone (OP) and obesity-resistant (OR) populations. RG rates and RFC were calculated weekly. Following the study, an adiposity index was calculated and arcuate nucleus (ARC) NPY expression was determined by in situ hybridization (ISH) or ribonuclease protection (RPA) assays. Results: Body weights were greater in OP rats after 2 weeks on the diet compared to OR rats and remained different throughout the study. RG and RFC were greater in OP rats compared to OR rats only during the first 2 weeks of the study. Leptin concentrations rose in both groups during the experiment, but the increase was greater in OP rats than in OR rats. Insulin changes paralleled those for leptin. ARC NPY mRNA expression was not different between OP and OR rats as measured by ISH and RPA. Discussion: Although NPY expression has been reported to be different initially in OP and OR rats, this difference dissipates following divergence of body weight. RFC and RG data suggest the initial NPY elevation may contribute to increased weight gain of OP rats during the first 2 weeks of the diet. Higher relative leptin concentrations in OP rats may be necessary to normalize differences in adiposity and apparent leptin and insulin resistance of OP rats.     

Serum Leptin Concentration and Insulin Sensitivity in Men with Abdominal Obesity

JOHANNSSON, GUDMUNDUR, CECILIA KARLSSON, LARS LÖNN, PER MÅRIN, PER BJÖRNTORP, LARS SJÖSTRÖM, BJÖRN CARLSSON, LENA M.S. CARLSSON, BENGT-ÅKE BENGTSSON. Serum leptin concentration and insulin sensitivity in men with abdominal obesity. Obes Res. 1998;6:416–421. Objective : We have examined the association between generalized adiposity, abdominal adiposity, insulin sensitivity, and serum levels of leptin in a cross-sectional study of abdominally obese men. Research Methods and Procedures : Thirty men, 48 to 66 years of age with a body mass index (BMI) of between 25 kg/m² and 35 kg/m² and a waist hip ratio of <0.95, were included in the study. Serum leptin concentration was measured using radioimmunoassay. Total body fat percentage was determined from total body potassium, abdominal adiposity was measured by computed tomography, and the glucose disposal rate (GDR) was measured during an euglycemic, hyperinsulinemic glucose clamp. Results : Significant correlations were found between serum leptin concentration and BMI, percentage body fat, abdominal subcutaneous adipose tissue, serum insulin, GDR, and 24-hour urinary-free Cortisol. In a multiple regression analysis, it was shown that abdominal subcutaneous adipose tissue, GDR, and BMI explained 72% of the variability of serum leptin concentration. GDR demonstrated an independent inverse correlation with serum leptin concentration. Discussion : In abdominally obese men with insulin resistance, it was demonstrated that most of the individual variability in serum leptin concentration was explained by the amount of subcutaneous abdominal adipose tissue, insulin sensitivity, and BMI.     

Leptin Receptor Gene in a Large Cohort of Massively Obese Subjects: No Indication of the fa/fa Rat Mutation. Detection of an Intronic Variant with No Association with Obesity

The massive obesity caused in rodents by the disruption of the leptin-receptor signal through genetic defects at the level of either leptin (OB) or leptin receptor (OB-R) has raised the question of the relevance of these genes to morbid obesity in humans. In this study, we screened a large population of massively obese subjects for the presence of a leptin receptor mutation homologous to that of fa/fa rats, a single base substitution changing glutamine 269, a highly conserved glutamine found at position 270 in the human sequence. After polymerase chain reaction (PCR) amplification of a DNA region encompassing the end of exon 5, intron 5, and the beginning of exon 6, we performed restriction fragment length polymorphism analysis. Within the limitations of this approach where only mutations introducing restriction sites (5 of 8 possibilities) could be assessed, no evidence of mutation at the codon gin 270 was found in 343 massively obese subjects. However, a new OB-R gene variant in intron 5 was revealed by Maell digestion of the PCR products. MaelVhOB-R genotyping revealed no difference in the distribution of the genotypes between obese subjects and a group of 79 unrelated non-obese control subjects. In addition, no significant association between various obesity-related metabolic phenotypes and the presence of MaeII/hOB-R alleles was found. Thus, our results did not support a significant role for the Maell/hOB-R gene variant in the development of the obese phenotype in the population we studied.     

Relationships of Plasma Leptin Levels to Changes in Plasma Free Fatty Acids in Women Who Are Lean and Women Who Are Abdominally Obese

HENNES, MAGDA MI, ARNAVAZ DUA, DIANA L MAAS, GABRIELE E SONNENBERG, GLENN R KRAKOWER, AHMED H KISSEBAH. Relationships of plasma leptin levels to changes in plasma free fatty acids in women who are lean and women who are abdominally obese. Regulation of leptin production by the hormonal and metabolic milieu is poorly understood. Because abdominal obesity is commonly associated with elevated plasma free fatty acid (FFA) flux, we examined the effects of augmenting FFA on plasma leptin levels in women who were lean and of suppressing FFA in women with abdominal obesity. In study 1, nine subjects who were lean, after a 12-hour overnight fast, received either intravenous saline or Intralipid plus heparin to increase the plasma FFA concentration to approximately 1000 μmol/ L. After 3 hours of additional fasting, subjects underwent 3-hour hyperglycemic clamps. In study 2, seven subjects with abdominal obesity were evaluated by a similar protocol, but lipolysis and plasma FFA flux were instead maximally suppressed by acipimox. In the individuals who were lean, leptin levels were unchanged during clamping. Increasing plasma FFA reduced plasma leptin from 7.66 ± 0.66 to 7.05 ±0 0.66 (p=0.03), but 3 hours of hyperglycemia plus hyperinsulinemia had no additional effect on leptin levels (7.15 ± 0.71). Basal leptin levels, 4-fold higher in the subjects with obesity, were reduced from 34.6 ± 2.4 μg/L to 32.3 ± 1.1 μg/L (p=0.004) during the clamp period. When plasma FFA flux was suppressed, however, plasma leptin levels after clamped hyperglycemia/hyperinsulinemia were increased to 38.9 ± 1.2 μg/L (p=0.014 vs. time 0 and 0.001 vs. saline protocol). Changes in leptin concentrations are not correlated with changes in FFA. These results suggest that plasma FFA concentration does not regulate plasma leptin levels in basal, extended fasting, or hyperglycemic/hyperinsulinemic states.     

Long-term Effects of Water-soluble Corn Bran Hemicellulose on Glucose Tolerance in Obese and Non-obese Patients: Improved Insulin Sensitivity and Glucose Metabolism in Obese Subjects

We examined the effect of soluble corn bran hemicellulose (CBH, 10g/day) on glucose control and serum insulin in three groups: patients with impaired glucose tolerance (IGT) with (20 subjects) or without (8 subjects) obesity and with healthy non-obese controls (10 subjects). Long-term supplementation (6 months) with CBH decreased the post oGTT curve for patients with impaired mild Type II diabetes, but not that for the controls. Hemoglobin A_1c decreased significantly during CBH supplementation in the obese patients, while the fasting glucose level decreased in all three groups, although not significantly. A decreased serum insulin response by oGTT was found in those patients with IGT.

The improved oGTT result was associated with improved insulin release and perhaps with peripheral insulin sensitivity. These findings suggest that CBH at a low dose might contribute to glycemic control and would play a useful role in treating Type II diabetes patients.     

Fiber Intake of Normal Weight,Moderately Obese and Severely Obese Subjects

ALFEERI, MARGARET AH, JOCELINE POMERLEAU, D MICHAEL GRACE AND LORRAINE ANDERSON. Fiber intake of normal weight, moderately obese and severely obese subjects. Obes Res. The lack of dietary fiber may be a contributing factor in obesity. This study examined the fiber intake of three weight groups: normal (20.0≤BMI≤27.0), moderately obese (27.1≤BMI≤39.9) and severely obese (BMI≥40.0). Each group contained 50 subjects. Detailed 3-day food records were used to gather the nutritional data. Fiber intake in the normal weight group was 18.8 ± 9.3 grams, the moderately obese consumed 13.3 ± 5.8 grams of fiber and the severely obese 13.7 ± 5.7 grams. Total fiber intake in grams was found to be significantly higher in the lean group (p<0.05) and was positively associated with sex and education level with men and more highly educated individuals consuming more fiber. Using regression analysis total fiber in grams and fiber in g/1000 kcalories was inversely associated with BMI after adjusting for sex, age, education level and income (p<0.01). A high fiber diet may help to promote a negative energy balance by causing early satiety secondary to gastric distention. Dietitians and physicians need to emphasize the importance of a high fiber diet to their obese patients.